Thiophene-carboxamide derivatives and their use as inhibitors of the enzyme IKK-2
a technology of carboxamide and inhibitor, which is applied in the field of thiophene carboxamide derivatives, can solve the problem that the nik cannot directly phosphorylate the ikk-2 enzyme, and achieve the effect of reducing the risk and reducing the risk of inflammatory diseases
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example 2
2-[(Aminocarbonyl)amino]-5-{4-[(isopropylamino)methyl]phenyl}thiophene-3-carboxamide
a) N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]propan-2-amine
[0170]Isopropylamine (0.5 ml) was added dropwise to a solution of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 g) in dimethoxymethane (10 ml) and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure and used immediately.
b) 2-[(Aminocarbonyl)amino]-5-{4-[(isopropylamino)methyl]phenyl}thiophene-3-carboxamide
A solution of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]propan-2-amine (0.46 g), 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxamide (0.2 g) and sodium carbonate (0.32 g) in a DME (15 ml) / water (1.5 ml) mixture was heated to 80° C. under an argon stream. Tetrakis-(triphenylphosphine)palladium(0) (5.1 g) was then added and the reaction was stirred at 90° C. for 4 h, cooled and evaporated under reduced pressure. Th...
example 3
2-[(Aminocarbonyl)amino]-5-{4-[(bis-(2-methoxyethyl)amino)methyl]phenyl}thiophene-3-carboxamide
a) N-(4-Bromobenzyl)-2-methoxy-N-(2-methoxyethyl)ethanamide
[0171]Di-(2-methoxyethyl)amine (6 ml) was added to a solution of 4-bromobenzylbromide (5 g) in DMF (20 ml) at ambient temperature. After stirring at ambient temperature for 2 h, the mixture was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic phase was dried, the solvent removed under vacuum to yield a yellow oil which was purified by column chromatography using a 0 to 20% ethyl acetate / isohexane gradient to yield the title compound as a clear oil (4.83 g). MS (M+H)+302.
1H NMR (CDCl3) 2.72 (t, 4H), 3.3 (s, 6H), 3.45 (t, 4H), 3.64 (s, 2H), 7.21 (d, 2H), 7.41 (d, 2H).
b) 2-[(Aminocarbonyl)amino]-5-{4-[(bis-(2-methoxyethyl)amino)methyl]phenyl}-thiophene-3-carboxamide
A solution of N-(4-bromobenzyl)-2-methoxy-N-(2-methoxyethyl)ethanamide (1.6 g) in THF (15 ml) was cooled to −60° C. under arg...
example 4
2-[(Aminocarbonyl)amino]-5-{4-[(N-ethyl-N-(2-methoxyethyl)amino)methyl]phenyl}thiophene-3-carboxamide
a) The title compound was made from N-(4-bromobenzyl)-N-(2-ethoxyethyl)ethanamine in a similar manner to Example 3 (b) except that it was purified by ion exchange chromatography to yield a cream solid (0.18 g).
MS (M+1)+ 377.
1H NMR (DMSO-D6) 0.97 (t, 3H), 2.48 (q, 2H obscured), 2.57 (t, 2H), 3.2 (s, 3H), 3.39 (t, 2H), 3.55 (s, 2H), 6.91 (bs, 2H), 7.21-7.31 (m, 3H), 7.44 (d, 2H), 7.62-7.69 (m, 2H), 10.97 (bs, 1H).
b) N-(4-Bromobenzyl)-N-(2-methoxyethyl)ethanamine
[0172]4-Bromobenzylbromide (4.01 g) was added to a solution of N-(2-ethoxyethyl)ethanamine (3.64 g) in DMF (40 ml). After stirring at ambient temperature for 18 h, the mixture was partitioned between diethyl ether and water. The organic phase was extracted with 2N aqueous hydrochloric acid which was then taken to pH 10 by addition of 2N sodium hydroxide solution. This was then extracted with diethyl ether which was dried and the...
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